1. NAME1.1 SubstancePromethazine
(INN, 1992)
Promethazine hydrochloride
(BAN, 1994; USAN, 1994)
Promethazine theoclate
(BAN, 1994)
1.2 Group
Antihistamines for systemic use (R06)/Phenothiazine
derivatives (R06AD)
(ATC classification index [WHO] 1992])
1.3 SynonymsDiprazinum; Proazamine Chloride; Promethazini Hydrochloridum;
Promethazinium Chloride.
1.4 Identification numbers1.4.1 CAS number
Promethazine 60-87-7
Promethazine 58-33-3
Hydrochloride
Promethazine 17693-51-5
theoclate
1.4.2 Other numbers
RTECS
Promethazine S06825000
Promethazine S08225000
hydrochloride
1.5 Brand names, Trade namesMonocomponent products
Avomine Daralix Fargan
Meth-zine Phenergan Prohist
Promet Quadnite Sayomol
Sominex ZiPan
Combination products
Phensedyl Linctus
Phenergan with codeine
Tixylix Linctus
Phenergan VC
Phenergan with dextromethorphan
(To be completed by each Centre using local data)
1.6 Manufacturers, Importers
Atosil (Tropon, W.Ger)
Fenazil (Sella, Ital.)
Meth-zine (Protea, Austral.)
Phenergan (May and Baker, Australia, U.K.; Rhone-Poulenc,
Canada, Denmark, France, Switzerland, Wyeth, U.S.A.)
(To be completed by each Centre using local data)
1.7 Presentation, Formulation
Preparations are usually formulated as promethazine
hydrochloride although promethazine theoclate tablets are
also available. The topical cream is formulated as free
promethazine.
Tablets 12.5 mg to 50 mg
Syrup 1.25 to 25 mg/5mL
Injection 25 to 50 mg/mL
Suppositories 12.5 to 50 mg
Formulations containing combinations of promethazine
hydrochloride and other drugs used to treat the symptoms of
coughs and colds are also available, e.g.
Phenergan with codeine (Promethazine 6.25 mg and 10 mg
codeine per 5 mL syrup)
Phenergan VC (Promethazine 6.25 mg and 5 mg phenylephrine per
5 mL syrup)
Phenergan with dextromethorphan (Promethazine 6.25 mg and
15 mg per 5 mL syrup)
The above syrups also contain approximately 7% ethanol.
Phensedyl (Promethazine 3.6 mg, codeine 9 mg, ephedrine
7.2 mg per 5 mL)
Tixylix (Promethazine 1.5 mg, pholcodine 1.5 mg per 5 mL)
(To be completed by each Centre using local data)
2. SUMMARY2.1 Main risks and target organs
Promethazine is a phenothiazine derivative with potent
antihistaminic properties. In therapeutic doses, CNS
depression manifested by sedation is a frequent occurrence.
In adults, overdosage is usually characterized by CNS
depression resulting in sedation and coma sometimes followed
by excitement.
In young children CNS stimulation is dominant, symptoms
include excitation, hallucinations, dystonias and
occasionally seizures.
Anticholinergic manifestations such as dry mouth, mydriasis
and blurred vision are usually present.
Overdosage may also present with various cardiorespiratory
symptoms such as respiratory depression, tachycardia,
hypertension or hypotension and extrasystoles.
2.2 Summary of clinical effectsToxic Reactions from Promethazine Central nervous system
Depression and/or stimulation. Sedation, coma, confusion,
disorientation. Hallucinations, hyperreflexia, toxic
psychoses, seizures. CNS excitation predominates in young
children.
Respiratory
Respiratory depression can occur.
Cardiovascular
Tachycardia, bradycardia, hypertension, hypotension,
extrasystoles.
Dermatological
Allergic contract dermatitis and photoallergy.
Head, Eye, Ear, Nose and Throat
Fixed or dilated pupils, blurred vision, diplopia. Dry
mouth, nasal stuffiness.
Others
Urinary retention, constipation. Hyperpyrexia has been
reported.
2.3 Diagnosis
Antihistamine poisoning must always be considered in patients
presenting with a central anticholinergic syndrome.
Concentrations of promethazine in blood and urine can be
determined by reverse phase HPLC (Taylor & Houston 1982).
2.4 First aid measures and management principles
Symptomatic supportive therapy is indicated including
artificial respiration if necessary. Although the
anticholinergic actions of promethazine reduce gastric
motility, gastric emptying should be considered should be
considered within 1 to 2 hours after ingestion.
Although emesis is recommended in many literature reports,
and is a useful first aid measure providing the patient is
conscious, gastric lavage is preferable as the effectiveness
of Ipecac Syrup may be reduced by the anticholinergic actions
of promethazine. If the patient is comatose or convulsing,
an endotracheal tube with cuff inflated must be in place to
prevent aspiration of vomitus.
Activated charcoal may also be administered. The use of a
cathartic is no longer recommended.
Hypotension should be controlled with fluids, posture and
pressor drugs such as dopamine or norepinephrine
(noradrenaline) if necessary.
Seizures may respond to intravenous diazepam. Phenytoin has
also been used.
In the presence of severe anticholinergic effects, seizures,
hallucinations, delirium, coma, hypertension and arrhythmias
have responded to intravenous physostigmine (Cowen, 1979;
Cleghorn & Bourke, 1980). However, the use of physostigmine
is considered controversial due to possibly toxic cholinergic
effects (see 10.6).
3. PHYSICO-CHEMICAL PROPERTIES 3.1 Origin of the substance
Synthesised from 10-phenothiazinepropyl chloride and
dimethylamine in the presence of Cu (U.S. patent 2,530,451;
1950 to Rhone-Poulenc). From Grignard complexes of
dimethylaminopropyl halide and phenothiazine (U.S. patent
2,607,773;1952 to Rhone-Poulenc), (Merck Index, 1983).
3.2 Chemical structure Structural formula Molecular formula
Promethazine C17H20N2S
Promethazine C17H20N2S,HCl
Hydrochloride
Promethazine C17H20N2S,C7H7ClN4O2
theoclate
Molecular weight
Promethazine 284.4
Promethazine 320.9
Hydrochloride
Promethazine 499.0
theoclate
Chemical names
1,N,N-Trimethyl-2-(phenothiazin-10-yl)ethylamine.
10-[2-(Dimethylamino)propyl]-phenothiazine monohydrochloride.
N,N,alpha-Trimethyl-10H-phenothiazine-10-ethanamine.
10-(2-dimethylamino-2-methylethyl)phenothiazine.
N-(2'-dimethylamino-2'-methyl)ethylphenothiazine.
(Martindale, 1993; Merck Index, 1993)
3.3 Physical properties 3.3.1 Properties of the substance
3.3.1.1 Colour (Hydrochloride)
White or faintly yellow. On prolonged exposure
to air it is slowly oxidised, becoming blue in
colour.
3.3.1.2 State/Form (Hydrochloride)
Crystalline powder
3.3.1.3 Description (Hydrochloride)
Odourless or almost odourless.
A 10% solution in water has a pH of 4.0 to 5.0.
Solubility
1 in 0.6 of water
1 in 9 of alcohol
1 in 2 of chloroform.
Practically insoluble in ether and acetone.
Melting point is about 222 °C.
Melting point (promethazine) is about 60 °C.
(Martindale, 1993)
3.3.2 Properties of the locally available formulation(s)
To be completed by each Centre using local data
3.4 Other characteristics3.4.1 Shelf-life of the substance
Expiry dates of the commercially available preparation
vary between 2 to 5 years.
3.4.2 Shelf-life of the locally available formulation(s)
Expiry dates of commercially available preparations
vary between 2 to 5 years depending on dosage form and
manufacturer (AHFS, 1988).
(To be completed by each Centre using local data).
3.4.3 Storage conditions
All preparations should be protected from light. Oral
and parenteral preparations of the drug should be
stored at a temperature of 15 to 30 °C, and the rectal
suppositories at 2 to 8 °C.
Freezing of the oral solution and injection should be
avoided.
The tablets and solutions of promethazine should be
stored in tightly closed, light resistant containers
and the rectal suppositories stored in well closed
containers. (AHFS, 1988)
3.4.4 Bioavailability
To be completed by each Centre using local data.
3.4.5 Specific properties and composition
To be completed by each Centre using local data. 4. USES 4.1 Indications 4.1.1 Indications
Promethazine is used for the treatment of allergic
symptoms, often given at night because of its marked
sedative effects. Drug hypersensitivity reactions have
also been treated with promethazine (Weil, 1968).
Promethazine is usually given orally for the treatment
of allergic conditions but can be given by deep
intramuscular injection or slow intravenous injection
in emergencies.
Promethazine is sometimes used for its sedative effects
and in some countries is marketed for this purpose,
including the sedation of young children.
Promethazine is used as an anaesthetic premedication to
produce sedation, reduce anxiety and also to reduce
post operative nausea and vomiting. The drug is often
given in conjunction with an opiate analgesic such as
pethidine, particularly in obstetrics.
Taken before travelling, promethazine is effective in
preventing motion sickness. Vomiting from other causes
can be treated with higher or more frequent doses.
Other less common uses
Promethazine has been used to control extrapyramidal
disorders in children caused by metoclopramide
(Stonham, et al., 1984) and levodopa induced
dyskinesias in patients with Parkinson's disease (Tarsy
et al., 1975).
In young children undergoing dental procedures it has
been suggested (Houpt et al., 1985) that promethazine
be used in conjunction with chloral hydrate to produce
sedation as there was a lower incidence of nausea than
when chloral hydrate was administered alone.
In some countries, promethazine is available as a 2%
cream for the treatment of allergic skin conditions,
however topical use is not recommended due to skin
sensitization reactions (Martindale, 1989).
4.1.2 Description
Not relevant
4.2 Therapeutic dosage4.2.1 Adults
Oral Hypersensitivity reactions (hydrochloride)
25 mg to 75 mg as a single dose at night; or
Up to 60 mg per day in divided doses.
Hypnotic (hydrochloride)
20 mg at night.
Nausea and vomiting (hydrochloride, theoclate)
Up to 25 mg every 4 to 6 hours.
Rectal
Doses similar to oral doses.
Parenteral All indications except nausea and vomiting (hydrochloride)
25 to 50 mg (Maximum of 100 mg per 24 hours)
(Intravenously/Intramuscularly).
Nausea and vomiting (hydrochloride)
12.5 to 25 mg every 4 hours (Maximum of 100 mg per 24
hours) (Intravenously/Intramuscularly).
(Martindale , 1993)
4.2.2 Children
Oral Hypersensitivity reactions (hydrochloride)
2 to 5 years 5 to 15 mg daily.
5 to 10 years 10 to 25 mg daily.
Hypnotic (hydrochloride)
2 to 5 years 15 to 20 mg at night.
5 to 10 years 20 to 25 mg at night.
Motion sickness(hydrochloride)
2 to 5 years 5 mg
5 to 10 years 10 mg
Motion sickness(theoclate)
5 to 10 years 12.5 mg
Parenteral Intramuscular All indications (hydrochloride)
5 to 10 years 6.25 to 12.5 mg
(Martindale, 1993)
Intravenous
A suggested maximum recommended intravenous dose for
patients under the age of seventeen is 0.5 mg/kg/dose
(ASHP, 1984).
4.3 Contraindications
Newborn and premature infants
Lactation
As a treatment for asthma
Patients receiving large doses of other CNS depressants or
patients who are comatose.
Hypersensitivity to promethazine and other phenothiazines.
Patients receiving therapy with monoamine oxidase inhibitors
(MAOI).
Patients with narrow angle glaucoma, stenosing peptic ulcer,
pyoloroduodenal obstruction, symptomatic prostatic
hypertrophy, bladder neck obstruction.
Because of a possible link between phenothiazine use and
Sudden Infant Death Syndrome of infant sleep apnoea,
authorities in the U.S. have stated that promethazine is
contraindicated in children under two years of age.
Precautions
Promethazine should be used with caution in patients with
impaired liver function, a history of bronchial asthma,
increased intraocular pressure, hyperthyroidism,
cardiovascular disease, hypertension and diabetes. Epileptic
patients may experience an increase in the severity of
seizures when treated with promethazine and the drug may be
contraindicated in these patients.
The drug should be used in dehydrated children or children
with acute infections due to increased susceptibility to
dystonias (AFHS, 1988).
Concurrent administration of promethazine with alcohol or
other CNS depressants will cause increased drowsiness.
Promethazine should be used in pregnancy only when the
potential benefits justify the possible risks to the foetus.
5. ROUTES OF ENTRY 5.1 Oral
Tablets
Solution
Syrup
Elixir
5.2 Inhalation
No data available.
5.3 Dermal
Topical cream.
5.4 Eye
No data available.
5.5 Parenteral
Preparations available for intramuscular and intravenous
injection.
5.6 Other
Rectal suppositories are available in some countries.
6. KINETICS6.1 Absorption by route of exposure
The drug is well absorbed from the gastrointestinal tract.
Peak plasma concentrations occur after 2 to 3 hours when
promethazine is administered orally (25 to 50 mg) or
intramuscularly (25 mg) (Digregorio & Ruch, 1980; Moolenaar
et al., 1981; Schwinghammer et al., 1984(i)).
Following rectal administration of promethazine in a
suppository formulation, peak plasma concentrations were
observed after about 8 hours (Schwinghammer et al., 1984(i)).
Oral bioavailability is approximately 25% (Taylor et al.,
1983). Rectal bioavailability has been reported at 23%
(Schwinghammer et al., 1984(i)).
6.2 Distribution by route of exposure
Promethazine is widely distributed in body tissues and has a
large apparent volume of distribution following oral and
intramuscular administration (DiGregorio & Ruch, 1980). In a
study involving seven adults the steady state volume of
distribution following intravenous administration was
reported to be 970 L (Taylor et al., 1983).
Promethazine has been reported to be 93% protein bound when
determined by gas chromatography (Quin & Calvert, 1976) and
as 76 to 80% protein bound when determined by HPLC
(Digregorio & Ruch, 1980).
Promethazine rapidly crosses the placenta, appearing in the
cord blood within 1.5 minutes when given intravenously at
term (Moya et al., 1963).
Promethazine crosses the blood brain barrier (Quach et al.,
1979).
6.3 Biological half-life by route of exposure
The elimination half life of promethazine following oral
administration has been estimated to be within the range of
12 to 15 hours (Taylor et al., 1979).
After intravenous administration of 12.5 mg, blood
concentrations of promethazine declined biexponentially with
a terminal elimination half life of 12 hours (Taylor et al.,
1983).
6.4 Metabolism
Promethazine is metabolized principally to promethazine
sulphoxide and to a lesser degree desmethylpromethazine. In
a study of 7 subjects, peak plasma concentrations of the
sulphoxide metabolite occurred earlier after oral
administration than after intravenous administration. It was
concluded that the major site of metabolism is the liver and
that the drug is subjected to extensive first-pass hepatic
biotransformation, explaining the oral bioavailability of
25%. Metabolism also occurs in the gut wall but to a lesser
degree than earlier postulated. The sulphoxide metabolite
has not been detected after intramuscular dosing as
circulating levels are probably below analytical detection
limits, due to a combination of slow absorption, lower dose
(50% of oral) and bypass of first pass metabolism in the
liver (Taylor et al., 1983).
6.5 Elimination by route of exposure
Elimination of promethazine is primarily due to hepatic
metabolism (see 6.4). In eight subjects given oral doses of
25 mg, only 0.6% of an administered dose was excreted
unchanged in the urine within 24 hours, while 10.3% was
excreted as promethazine sulphoxide (the major metabolite).
The renal clearance of the sulphoxide approached the GFR
being 90 mL/min while that of promethazine was only
5.9 mL/min, suggesting significant tubular reabsorption of
promethazine (Taylor et al., 1983). Most oxidised
metabolites of other phenothiazines are biologically inactive
(Goodman & Gilman, 1980). No evidence was found to suggest
that metabolites of promethazine are pharmacologically or
toxicologically active. Promethazine has not been reliably
detected in breast milk (Briggs et al., 1986).
7. PHARMACOLOGY AND TOXICOLOGY 7.1 Mode of action 7.1.1 Toxicodynamics
The pharmacology of promethazine is complex and for
this reason toxicological mechanisms are not completely
understood. Most reference texts suggest that the
toxicity of promethazine is mainly due to its
anticholinergic actions at muscarinic receptors. Many
of the signs and symptoms of poisoning are similar to
those observed with atropine. In the presence of
anticholinergic effects, serious manifestations such as
seizures, hallucinations, hypertension and arrhythmias
have been reversed (in some cases) by the
administration of physostigmine.
As well as anticholinergic effects, promethazine can
also exhibit toxic effects typical of antipsychotic
phenothiazines. Hypotension and extrapyramidal signs
may be attributable to antidopaminergic actions of
promethazine.
7.1.2 Pharmacodynamics
Promethazine is a phenothiazine antihistamine,
antagonizing the central and peripheral effects of
histamine medicated by histamine H1 receptors. The
drug does not antagonize histamine at H2 receptors.
Antihistamines competitively antagonize most of the
smooth muscle stimulating actions of histamine on the
H1 receptors of the gastrointestinal tract, uterus,
large blood vessels and bronchial muscle. Increased
capillary permeability and oedema formation, flare and
pruritus, resulting from actions of histamine on H1
receptors, are also effectively antagonized.
Promethazine appears to act by blocking H1 receptor
sites, preventing the action of histamine on the cell.
Promethazine rapidly crosses the blood brain barrier
and it is thought that the sedative effects of
antihistamines are due to blockade of H1 receptors in
the brain (Quach et al., 1979).
Promethazine is not used clinically for its
antipsychotic properties but in common with other
phenothiazines exhibits antidopaminergic properties.
The antiemetic effect of promethazine may be due to
blockade of dopaminergic receptors in the Chemoreceptor
Trigger Zone (CTZ) of the medulla.
Promethazine has strong anticholinergic properties,
blocking the responses to acetylcholine that are
mediated by muscarinic receptors. These atropine-like
actions are responsible for most of the side effects
observed in clinical use of the drug. Promethazine
also has anti-motion sickness properties which may be
due to central antimuscarinic action.
In concentrations several times higher than those
required to antagonize histamine, promethazine exhibits
local anaesthetic effects. Promethazine has also been
shown to inhibit calmodulin (Levin & Weiss, 1976).
Authors have suggested (Peachell & Pearce, 1985) that
calmodulin inhibition by promethazine could be a
mechanism involved in the blockade of histamine
secretion at cellular level.
7.2 Toxicity 7.2.1 Human data
7.2.1.1 Adults
Minimum lethal exposure and maximum tolerated
exposure have not been clearly defined in human
subjects, due mainly to the lack of data on the
exact amount ingested in cases of overdosage.
Peak plasma levels following therapeutic oral
doses of 30 to 50 mg in adults have ranged from
11 to 23 ng/mL (Wallace et al., 1981).
Adverse effects following intramuscular
injection were associated with plasma levels of
48 ng/mL (Schwinghammer et al., 1984(i)).
7.2.1.2 Children
Promethazine is readily available in syrup form
which is often administered to sedate young
children. It is likely that in many cases the
dose is excessive, leading to symptoms of
toxicity.
CNS toxicity with survival has been reported in
children aged 5 to 12 years after accidental
ingestion of 200 to 500 mg of promethazine
(12.5 to 28 mg/kg). (Leak & Carroll, 1967;
Cleghorn & Bourke, 1980.)
Death was reported in a two-year-old child with
a history of ingesting 200 mg of promethazine
as tablets (Dominikovich, 1962).
Death was reported in an infant with a post
mortem blood level of 156 ng/mL (Degouffe &
Rice, 1982).
TDLo (child, oral) 20 mg/kg
Behavioral (excitement,
change in motor
activity, stiffness)
TDLo (Human) 3500 ug/kg/D.
Behavioral (sleep,
convulsions, rigidity)
7.2.2 Relevant animal data
LD50 (mouse, intravenous)55 mg/kg
7.2.3 Relevant in vitro data
No data available.
7.3 Carcinogenicity
Long-term animal studies to determine the carcinogenic
potential of promethazine have not been performed at the time
of preparation of this Monograph. There are no human or
animal data concerning the carcinogenic potential of the
drug. As phenothiazines induce prolactin secretion by
inhibiting dopamine, investigations have been carried out to
ascertain whether there is a correlation between chronic
phenothiazine administration and the development of pituitary
tumours. In two studies, (Asplund et al., 1982; Lilford et
al., 1984) the results were inconclusive and further in-depth
studies are necessary to evaluate the potential for
phenothiazines to induce pituitary adenomas.
7.4 Teratogenicity
A number of investigations have been performed to assess the
teratogenic potential of promethazine (Heinonen et al., 1977;
Wheatley, 1964; Greenberg et al., 1977). These studies
failed to show and association between promethazine exposure
in the first trimester of pregnancy and malformations.
Current opinions is that these studies were not adequate or
sufficiently controlled to establish whether promethazine is
safe to use in pregnancy with respect to possible adverse
effects on the fetus (AHFS 1988). Use late in pregnancy may
result in EEG changes in the neonate (Borgstedt & Rosen,
1968). Promethazine has not been shown to be teratogenic in
rats receiving oral doses of 6.25-12.5 mg/kg daily (2-4 times
the maximum recommended human dosage) (AHFS, 1988).
Promethazine should be used in pregnancy only when the
potential benefits justify the possible risks to the fetus.
7.5 Mutagenicity
There was no evidence of promethazine induced mutagenesis in
the Ames microbial mutagen test (AHFS, 1988). No relevant
human or animal data available to date.
7.6 Interactions
Concomitant administration of promethazine and other CNS
depressants (ethanol, narcotics, other phenothiazines and
antihistamines, barbiturates and benzodiazepines) may lead to
excessive CNS depression and possible respiratory depression.
The combination of promethazine and tricyclic antidepressant
drugs (e.g. amitriptyline, doxepin) or other drugs with
anticholinergic actions, may result in additive
anticholinergic effects (Hansten & Horn, 1989). Many
preparations containing promethazine also contain other
drugs, such as codeine, dextromethorphan, phenylephrine and
ephedrine. The toxic effects of these drugs must be
considered if compound preparations have been ingested.
7.7 Main adverse effects
Sedation, ranging from mild drowsiness to deep sleep, is
probably the most common adverse effect.
Anticholinergic effects such as dryness of the mouth, nose
and throat, blurred vision, mydriasis, poor accommodation,
sweating and thickening of bronchial secretions are frequent.
Dizziness, lassitude, disturbed co-ordination and muscular
weakness have all be reported.
Gastrointestinal effects including epigastric distress,
nausea, diarrhoea or constipation can occur.
Promethazine can also cause immunoallergic reactions.
Leucopenia and agranulocytosis (Engel, 1979) have occurred
rarely, and usually in patients receiving promethazine in
combination with other drugs known to cause these effects.
Jaundice and thrombocytopenic purpura have been reported
rarely.
Extrapyramidal effects can occur, especially at high doses.
Cardiovascular side effects are occasionally seen after
injection; tachycardia, bradycardia, mild transient
hypertension and hypotension have all been noted (Martindale,
1989).
Venous thrombosis has been reported at the site of
intravenous injections. Arteriospasm and gangrene may follow
inadvertent intra-arterial injection (Mostafavi & Samimi,
1971).
Respiratory depression, sleep apnoea and sudden infant death
syndrome (SIDS) have occurred in a number of infants or young
children who were receiving usual doses of promethazine.
(Kahn & Blum, 1979 and 1982; Kahn et al., 1985). These
reports suggest that promethazine and other CNS depressants
may cause sudden death, especially in apnoea prone infants,
and that these drugs should be avoided in infants even though
a causal relationship has been established.
8. TOXICOLOGICAL AND BIOMEDICAL INVESTIGATIONS
The treatment of promethazine poisoning is symptomatic and
evaluation of drug level sin body fluids is not useful in guiding
therapy. Promethazine is unstable in aqueous and organic
solvents (Meaking et al., 1978) and, due to its large volume of
distribution, is present in very low concentrations in body
fluids. These factors have presented difficulties when
developing methods of the determination of promethazine in serum.
Gas chromatographic methods with flame ionization have been used
to detect toxic concentrations of the drug in serum (Wells et
al., 1975). Although increased sensitivity is obtained with
nitrogen specific gas chromatographic methods (Dadisch et al.,
1977). HPLC methods have been developed in order to carry out
pharmacokinetics studies (Digregorio & Ruch, 1980; Taylor &
Houston, 1982).
8.1 Sample 8.1.1 Collection
Blood should be placed in heparinised polycarbonate
tubes.
8.1.2 Storage
Blood and urine sample should be protected from light
and frozen at -20°C until assay.
8.1.3 Transport
Samples should be frozen and protected from light.
8.2 Toxicological Analytical Methods 8.2.1 Tests for active ingredient
Qualitative and quantitative tests are described in the
USP(XXII). Infra-red spectroscopy for identification
and non-aqueous titration with perchloric acid for
quantitative assay. Test and assay procedures should
be carried out rapidly and under subdued light.
8.2.2 Tests for biological sample
Simple urine colour tests are available to
qualitatively determine the presence of phenothiazines
in urine. Although these tests are not specific for
promethazine they may be useful in helping to confirm a
diagnosis. Test solution (FPN universal); 5 parts 5%
ferric chloride; 45 parts 20% perchloric acid; 50
parts 50% nitric acid. Mix 1 ml urine with l ml test
solution; read immediately; disregard all colours
appearing after a delay of 10 seconds or more.
Phenothiazines give colours ranging from peach, pink,
rose to purple and dark gray. An approximate
correlation is the darker the colour then the higher
the daily dose of phenothiazine (Ellenhorn & Barceloux,
1989). Promethazine and its metabolites can be
quantitatively determined in blood and urine by reverse
phase HPLC (Taylor & Houston, 1982).
Measuring blood levels of promethazine is not
considered to be of practical assistance in the
clinical management of promethazine poisoning.
8.3 Other laboratory analyses 8.3.1 Biochemical investigations
Regular laboratory investigations should be performed
to assure that liver function tests and electrolytes
remain within normal limits.
8.3.2 Arterial blood gas analyses
Not normally indicated.
8.3.3 Haematological or Haemostasiological investigations
Not specifically indicated.
8.3.4 Other relevant biomedical analyses
ECG may be useful if arrhythmias are suspected.
8.4 Interpretation 9. CLINICAL EFFECTS 9.1 Acute poisoning 9.1.1 Ingestion
Overdosage may result in CNS depression followed by
stimulation (excitation, agitation, hyperreflexia). In
young children or teenagers, CNS stimulation is usually
dominant. Symptoms resemble anticholinergic overdose
and may include fixed and dilated pupils, flushed face,
fever, dry mouth, excitation, hyperreflexia, dystonias,
hallucinations and tonic-clonic seizures. Periods of
excitation may alternate with somnolence and catatonia.
Hypertension or hypotension may be noted in agitated or
comatose patients respectively. Tachycardia and
extrasystoles have been reported (Shawn & McGuigan,
1984).
While coma appears to occur more frequently in adults,
it may do so because of co-ingestion of ethanol
(Jacobsen D, Personal communication).
9.1.2 Inhalation
No data available.
9.1.3 Skin exposure
Topical application of promethazine has resulted in
systemic toxic effects, especially in young children
(Shawn & McGuigan, 1984; Pan et al., 1989). Symptoms
reported include visual hallucinations, peripheral
anticholinergic signs, drowsiness, agitation,
irritability, tachycardia and myoclonus.
Topical application of promethazine may cause contact
dermatitis.
9.1.4 Eye contact
No data available.
9.1.5 Parenteral exposure
Rapid intravenous administration of promethazine may
cause hypotension (AHFS, 1988). Tachycardia,
bradycardia and faintness have all been reported with
parenteral promethazine.
Chemical irritation and necrotic lesions have resulted
on rare occasions following subcutaneous injection of
promethazine and the drug should not be administered by
this route. Extravasation should also be avoided.
Accidental intra-arterial injection can cause chemical
irritation and arteriospasm leading to impaired
circulation and gangrene. There are case reports of
amputation as a result of intra-arterial injection of
promethazine (Heber & Helmig, 1976).
9.1.6 Other
No data available.
9.2 Chronic poisoning 9.2.1 Ingestion
Promethazine has rarely been associated with
obstructive jaundice which is usually reversible if the
drug is discontinued (AHFS, 1988).
Leucopenia and agranulocytosis have been reported
rarely, usually in conjunction with other agents known
to have caused these effects.
Thrombocytopenic purpura has also been reported (AHFS,
1988). As with other phenothiazines, promethazine can
cause photosensitivity reactions. Long-term use of the
antipsychotic phenothiazines has been associated with
many adverse reactions including, blood dyscrasias,
hepatotoxicity, ocular changes, dermatological
disorders and allergic reactions. The possibility that
these could occur with prolonged administration of
promethazine should not be ruled out.
9.2.2 Inhalation
No data available.
9.2.3 Skin exposure
Topical administration of promethazine can cause
allergic reactions (contact dermatitis, pruritic),
inflammation and also photosensitivity.
9.2.4 Eye contact
No data available.
9.2.5 Parenteral exposure
Venous thrombosis has been reported at the site of
intravenous injections (Martindale, 1989).
9.2.6 Other
No data available.
9.3 Course, prognosis, cause of death
Mild cases of overdosage may manifest simply as excessive
drowsiness or mild CNS excitation in children or teenagers.
With increasing dose coma may develop, or more frank symptoms
of CNS excitation, for example, hallucinations, delirium,
hyperreflexia. There is little indication in the literature
that the severity of the poisoning can be related to the
appearance of signs and symptoms such as extrapyramidal
effects, hypertension or hypotension.
Treatment is symptomatic and the appearance of specific
effects cannot be relied upon when assessing the severity of
poisoning. It is generally agreed that as the severity of
the poisoning increases serious anticholinergic effects
usually appear along with seizures, hypertension and
arrhythmias, delirium or coma. Death due to respiratory
arrest has been reported in association with promethazine
poisoning (Dominikovich, 1962).
9.4 Systematic description of clinical effects
Since formulations containing promethazine in combination
with other drugs are available, it may alter the clinical
picture from the following description.
9.4.1 Cardiovascular
Acute Tachycardia and extrasystoles have been reported
(Pan et al., 1989). Hypotension, or even cardiac shock
may develop after antihistamine overdose. Hypertension
has also occurred.
9.4.2 Respiratory
Acute
Stridor, wheezing and bronchospasm have been reported
after a single 25 mg dose (ADRAC, 1982).
Respiratory arrest has been reported following overdose
(Darwish et al., 1980; Dominikovich, 1962).
Acute or chronic
The observation that promethazine (and other
phenothiazines) may increase the number of central and
obstructive sleep apnoeas has lead to speculation that
some cases of sudden infant death syndrome (SIDS) may
be related to promethazine therapy (Kahn & Blum, 1982).
The available data are suggestive, but inconclusive
that a causal relationship exists between therapeutic
promethazine administration and SIDS.
9.4.3 Neurological
9.4.3.1 Central nervous system (CNS)
Acute CNS depression commonly occurs early in
cases of overdosage. Drowsiness, confusion and
coma have all been reported (Leak & Carroll,
1967). Periods of CNS excitation may alternate
with somnolence and catatonia (Mantz et al.,
1964). Coma can occur in promethazine
overdose. A 14 year old boy became comatose
after ingesting 200 mg of promethazine (Pan et
al., 1989). CNS excitation often predominates
in children at the onset of poisoning and may
occur in adults, usually as the patient emerges
from coma. Patients may become agitated,
hyperreflexic, restless, delirious and nervous
(Leak & Carroll, 1967). Acute psychoses and
neurological reactions have been reported
following therapeutic use of promethazine
(Swaiman, 1960). A dose of 12.5 mg was
administered intramuscularly to a five-year-old
child, eighteen hours later the patient became
lethargic and experienced visual hallucinations
and muscular incoordination. Eventually the
child became comatose, a condition which
persisted for 28 hours. Another report (Jones
et al., 1973) cites the case of child given a
pre-operative dose of 20 mg of promethazine.
Within hours, the child experienced confusion,
hallucinations, agitation and complained of
worms crawling on the bedsheets. Visual and
tactile hallucinations have been associated
with promethazine toxicity (Shawn & McGuigan,
1984; Leak & Carroll, 1967). Similar symptoms
have been described after therapeutic use in
children (Kalikow & Kisco, 1988) and in adults
with renal failure (McAllister et al., 1978).
Acute extrapyramidal reactions following single
doses of promethazine have been reported.
Parkinsonism like symptoms were induced in an
adult male following an oral dose of 50 mg
(Schwinghammer et al., 1984(ii)).
Extrapyramidal reactions are more likely to
occur with high doses (AHFS, 1988). Seizures
can be a complication of promethazine
overdosage.
Cases of seizures have been reported in
children who received higher than recommended
doses of promethazine as an anaesthetic
premedication (Waterhouse, 1967).
Acute dystonic reactions including
opisthotonos, oculogyric crisis and facial
dyskinesias have occurred following
promethazine overdose. In one report, onset of
dystonias was delayed for 24 hours after a
large promethazine overdose (Darwish et al.,
1980). Other neurological effects associated
with promethazine poisoning:-
Extensor plantar reflexes (Leak & Carroll,
1967). Encephalopathy (25 mg rectal dose to a
five year old child) (Fisher, 1972).
Choreoathetosis. In one case movements did not
occur until 24 hours following overdosage
(Cleghorn & Bourke, 1980).
9.4.3.2 Peripheral nervous system
No data available.
9.4.3.3 Autonomic nervous system
No data available.
9.4.3.4 Skeletal and smooth muscle
No data available.
9.4.4 Gastrointestinal
The anticholinergic properties of the drug may cause
dry mouth and slow the rate of gastric emptying.
9.4.5 Hepatic
Chronic promethazine has rarely been associated with
obstructive jaundice which is usually reversible
following discontinuance of the drug (AHFS, 1988).
9.4.6 Urinary
9.4.6.1 Renal
Acute urinary retention due to anticholinergic
actions have been reported with promethazine
toxicity (Shawn & McGuigan, 1984).
9.4.6.2 Other
Promethazine overdose has reported to produce a
characteristic rose coloration of urine,
however this was due to haematuria in one case
(Cliche, 1961).
9.4.7 Endocrine and reproductive systems
Promethazine was considered to be unsafe in patients
with acute porphyria although there is conflicting
experimental evidence on porphyrinogenicity
(Martindale, 1989).
9.4.8 Dermatological
Acute or chronic
Urticaria has been reported following oral ingestion
(ADRAC, 1982). Photosensitivity (principally
photoallergic dermatitis) can occur following topical
or systemic administration of antihistamines, including
promethazine. The reaction may manifest as eczema,
pruritic, papular rash or erythema. Promethazine may
also cause sensitization following topical use, giving
rise to an allergic contact dermatitis (AHFS, 1988).
9.4.9 Eye, ear, nose throat: local effects
Acute
Anticholinergic effects on the eye include, mydriasis,
fixed pupils, blurred vision, diplopia and general
visual disturbances (Cowen, 1979; Shawn & McGuigan,
1984). Oculogyric crisis has been reported following
overdose (Darwish et al., 1980).
Dryness of the nose and nasal stuffiness have been
noted (Dominikovich, 1962; Leak & Carroll, 1967).
Anticholinergic effects include dryness of the mouth
and throat. Facial erythema has been noted (Cliche,
1961).
9.4.10 Haematological
Chronic leucopenia and agranulocytosis have been
reported rarely in patients receiving promethazine in
combination with other drugs known to cause these
effects. Thrombocytopenic purpura has been reported
with promethazine (AHFS, 1988). A case of allergic
agranulocytosis has been reported (Engel, 1976),
however this patient was taking larger than normal
doses, up to 400 mg per day, for approximately four
weeks. Discontinuing the promethazine resulted in the
eventual complete recovery of the patient.
Serious blood dyscrasia have occurred with the
antipsychotic phenothiazines and the possibility that
these could occur with promethazine should not be
discounted.
9.4.11 Immunological
There is a report of an acute anaphylactoid reaction
involving promethazine and temazepam (Mills, 1988)
although it was not established whether promethazine
was the causative agent.
Chronic promethazine is a potent sensitiser
particularly following topical application.
Promethazine can exert immunosuppressive effects
resulting in potentially adverse reactions, e.g.
infections (Descotes, 1988).
9.4.12 Metabolic
9.4.12.1 Acid-base disturbances
No data available.
9.4.12.2 Fluid and electrolyte disturbances
Hypokalaemia has been reported (Mantz et al.,
1964).
9.4.12.3 Others
Hyperthermia following promethazine ingestion
has been reported (Dollberg, 1980).
9.4.13 Allergic reactions
Photoallergic dermatitis can occur following topical
or systemic administration of promethazine. Topically
applied promethazine can cause allergic contact
dermatitis.
9.4.14 Other clinical effects
No data available.
9.4.15 Special risks
Pregnancy
Promethazine is commonly used in obstetrics as an
adjunct to opiate analgesia and as a sedative. The
drug rapidly crosses the placenta, appearing in cord
blood within one and a half minutes of an intravenous
dose (Moya & Thorndike, 1963). The use of
promethazine during labour has been associated rarely
with neonatal respiratory depression (Hall, 1987).
Transient behavioral and EEG changes have also been
described in neonates (Borgstedt & Rosen, 1986).
Promethazine has been shown to markedly impair
platelet aggregation in the newborn but less so in the
mother (Corby & Shulman, 1971; Whaun et al., 1980).
Immunological disturbances have been described in a
few infants whose mothers had been treated with
promethazine during pregnancy (Descotes, 1988). The
clinical significance of these effects are unknown.
A number of studies have been performed to assess the
teratogenic potential of promethazine (Heinonen et
al., 1977; Wheatley, 1964). The safe use of
promethazine during pregnancy has not been
established. The drug should only be used when the
potential benefits justify the possible risks to the
foetus.
9.5 Other
No data available.
9.6 Summary
Not relevant
10. MANAGEMENT10.1 General principles
Symptomatic supportive therapy is indicated and general
measures such as maintenance of adequate ventilation and
cardiovascular function must be instituted if necessary.
Gastric emptying may be successful, even if delayed for up
to 2 hours. Emesis should probably not be induced due to
the risk of coma or psychosis developing in the patient.
Administration of activated charcoal would be preferred.
The use of a cathartic is no longer recommended. In the
absence of seizures, gastric lavage (with endotracheal tube
with cuff inflated in place to prevent aspiration of
gastric contents) may be beneficial.
Seizures may be controlled with intravenous diazepam
(preferred) or phenytoin. Unless severe, hypotension
should be treated with posture; severe cases can be treated
with fluids, or pressor agents.
In severe hypertension, parenteral sodium nitroprusside may
be required. Dystonic reactions frequently respond to
intravenous diphenhydramine. In the presence of severe
anticholinergic effects, physostigmine by slow intravenous
injection, has been administered. However, the use of
physostigmine is considered controversial.
10.2 Relevant laboratory analyses
Treatment is symptomatic and supportive and measurement of
promethazine levels in body fluids is not useful in guiding
treatment of overdosage. No specific investigations are
indicated.
10.2.1 Sample collection
Venous blood samples are placed in heparinised
polycarbonate tubes and frozen at -20°C until assay.
Urine samples should be protected from light and
also stored at -20°C (Taylor et al., 1983)
10.2.2 Biomedical analysis
Concentrations of promethazine in blood and urine
can be determined by reverse phase HPLC (Taylor &
Houston 1982).
10.2.3 Toxicological analysis
Not relevant
10.2.4 Other investigations
Not relevant
10.3 Life supportive procedures and symptomatic/specific
treatment
General measures such as maintenance of ventilation and
cardiovascular function must be instituted if necessary.
Arrhythmias
Sinus tachyarrhythmias do not need to be routinely treated
unless the patient demonstrates signs or symptoms of
haemodynamic instability. Tachyarrhythmias may respond to
intravenous propranolol or another beta-blocker.
Seizures
Administer diazepam intravenously. If seizures are not
controlled or recur administer, intravenous phenytoin.
Dystonic reactions
Usually respond to intravenous diphenhydramine(to be used
only to treat severe reactions).
10.4 Decontamination
Following oral ingestion and parenteral exposure
The anticholinergic properties of promethazine slow gastric
motility, therefore gastric emptying may be considered up
to two hours following the ingestion.
Activated charcoal may be administered.
Following dermal exposure
The exposed area should be washed thoroughly with soap and
water.
10.5 Elimination
No reports in the literature were found to suggest that
forced diuresis, haemoperfusion or dialysis were of any
value.
10.6 Antidote treatment10.6.1 Adults
Physostigmine has been used intravenously to control
coma, hallucinations and delirium inpatients with
severe anticholinergic signs and symptoms (Cleghorn
& Bourke, 1980; Cowen, 1979). The use of
physostigmine is considered controversial due to the
possibility of hazardous cholinergic effects,
including convulsions (Meredith et al., 1984). It
should be considered if severe (central)
anticholinergic features are present. Atropine
should be readily available in case unwanted
cholinergic side-effects develop.
10.6.2 Children
As above, in 10.6.1.
10.7 Management discussion
Most authorities no longer recommend the use of
physostigmine as an antidote although there appears to be
some controversy in the literature.
Promethazine toxicity may well be an unrealized problem of
significant proportions, especially in developing countries
where promethazine containing preparations can be bought
and freely administered to young children. There is
probably scope for research into the significance of this
problem; methods of preventions and education of patients
and health care workers.
11. ILLUSTRATIVE CASES11.1 Case reports from literature Case 1 (Oral ingestion, child)
A two-year-old ingested up to 200 mg of promethazine in
tablet form. On admission he had a two-hour history or
rigidity and alternate tightening and loosening of the
hands. Restlessness, irritability, purposeless limb
movements and nasal congestion was also noted. Gastric
lavage was performed two and a half hours after admission
with no return of tablets. Three hours later the child
died of respiratory failure (Dominikovich, 1962).
Case 2 (Oral ingestion, child)
A twelve-year-old male developed delirium and
hallucinations four hours after the ingestion of 200 mg of
promethazine. Slurred speech, violent activity,
restlessness, agitation, tachycardia, dry mouth and nasal
stuffiness were also noted. Hallucination and extensor
plantar reflexes resolved 22 hours after onset (Leak &
Carroll, 1967).
Case 3 (Oral ingestion, adult)
A forty-year-old woman ingested an unknown amount of
promethazine. The patient was comatose on admission,
responding slightly to pain, with mydriasis and extensor
plantar reflexes. Six hours after admission she was
arousable but restless and aggressive. Twenty four hours
after admission she was experiencing hallucinations,
delirium and confusion which were resolved following a dose
of 0.5 mg physostigmine intramuscularly. By the following
day all symptoms had resolved (Cowen, 1979).
Case 4 (Topical application, child)
Application of 26 mg/kg of promethazine to 30% of total
body surface area to a sixteen-month-old boy resulted in
drowsiness within thirty minutes. The patient awoke two
hours after application but was irritable and ataxic. Six
hours later signs and symptoms included irritability,
drowsiness, agitation and tachycardia. All manifestations
resolved eighteen hours after exposure. A urine specimen
taken ten hours post-exposure did not contain promethazine
(Shawn & McGuigan, 1984).
Case 5 (Topical application, adolescent)
A fourteen-year-old boy presented unconscious five hours
after topical application of 90 g of 2% promethazine cream
to the entire body. Signs and symptoms on admission
included disorientation, agitation, myoclonus and dry
mouth. Blood and urine specimens on admission showed
140 ng/ml and 80 ng/ml or promethazine respectively. All
manifestations resolved within twenty four hours (Pan et
al., 1989).
Case 6 (Oral ingestion, adult, fatality)
A twenty-seven-year-old man died after taking a massive
overdose of promethazine tablets. Promethazine levels in
the body were approximately on thousand times the
therapeutic level. No other drugs or alcohol were detected
in the stomach contents or urine (Pharm J 1985).
11.2 Internally extracted data on cases
No data available.
11.3 Internal cases
To be completed by each Centre using local data.
12. ADDITIONAL INFORMATION12.1 Availability of antidotes
To be completed by each Centre using local data.
12.2 Specific preventive measures
Store in air-tight containers protected from light, in
child resistant packaging away from the sight and reach of
children.
12.3 Other
No data available.
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14. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE
ADDRESS(ES)
David J. WOODS BSc. MRPharmS.
Pharmacy Department
University of Otago Medical School
P.O. Box 913
Dunedin New Zealand
29th June 1990